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Journal of Clinical Oncology, Vol 22, No 9 (May 1), 2004: pp. 1630-1637 © 2004 American Society of Clinical Oncology. DOI: 10.1200/JCO.2004.09.070 Ten-Year Outcomes in a Population-Based Cohort of Node-Negative, Lymphatic, and Vascular Invasion–Negative Early Breast Cancers Without Adjuvant Systemic TherapiesFrom the Division of Medical Oncology, Breast Cancer Outcomes Unit, Division of Pathology and Division of Radiation Oncology, British Columbia Cancer Agency (BCCA), Vancouver and Victoria, Canada Address reprint requests to Stephen Chia, MD, Division of Medical Oncology, British Columbia Cancer Agency, 600 West 10th Ave, Vancouver, BC Canada, V5Z 4E6; e-mail: schia{at}bccancer.bc.ca
PURPOSE: To discuss the absolute benefits from adjuvant systemic therapy knowledge of long-term outcomes and baseline risks of relapse and disease-specific survival are required. We assessed the 10-year outcomes in a population-based cohort of node-negative (N–) lymphovascular negative (LV–) early breast cancers diagnosed from 1989 to 1991 who did not receive adjuvant systemic therapy. METHODS: One thousand one hundred eighty-seven cases of pT1–2N0 LV– breast cancers with a median follow-up of 10.4 years were reviewed. Kaplan-Meier survival curves for relapse free survival (RFS), breast cancer–specific survival (BCSS) and overall survival (OS) were compared with log-rank tests with cohorts stratified for tumor size and grade.
RESULTS: The median age of this series was 62 years. Four hundred thirty tumors were
CONCLUSION: This study provides detailed information on the continued relapse and breast cancer death rate to 10 years of follow-up. Specifically, without adjuvant systemic therapy, patients with LV–, N – breast cancer had a
Breast cancer screening has resulted in the diagnosis of greater numbers and proportions of pathologically node-negative breast cancers.1 Primary tumor characteristics are therefore increasingly important in the selection of patients to whom to recommend adjuvant systemic therapy. In a consensus statement from 1999 tumor size, histologic grade, histologic type, and hormone receptor status were categorized as most useful in clinical patient management.2 These prognostic factors predict the risk of relapse and are used to stratify patients for recommendations of adjuvant systemic therapy.3–5 Results derived from both individual randomized trials and from the meta-analyses by the Early Breast Cancer Trialists' Collaborative Group (EBCTCG) are routinely used in clinical practice in discussion with breast cancer patients considering adjuvant therapies. The EBCTCG meta-analyses demonstrated that a 35% relative risk reduction (RRR) in recurrence occurs with polychemotherapy, and a 47% RRR in recurrence is achieved with 5 years of tamoxifen.6–7 A corresponding 15% and 26% RRR in mortality with chemotherapy and hormonal therapy, respectively, can also be expected. However to calculate the absolute benefit of adjuvant therapy for an individual woman, the breast cancer specific outcome in an untreated population correlating to the specific pathologic characteristics of the individual's tumor is required. Breast cancer, especially node-negative at diagnosis, has a long natural history, so reliable outcomes at 10 years or more are required and should be presented in the context of other competing risks of mortality. This is a report of 10-year breast cancer outcomes in a population-based cohort of early breast cancer patients who did not receive adjuvant systemic therapy. Outcomes are stratified by tumor size and grade. The goal was to identify subgroups of patients with a very low risk of relapse, thus for whom adjuvant systemic therapy may potentially be avoided. Patients with involved axillary nodes or lymphovascular invasion were excluded because they are at sufficiently high enough risk of subsequent relapse to warrant adjuvant systemic therapy.8–10
Patients were identified from the Breast Cancer Outcomes Database (BCOD) maintained by the British Columbia Cancer Agency (BCCA). The BCCA has the mandate of cancer control for the province of British Columbia. This includes the operation of the four regional cancer centers delivering all the radiation therapy in the province, and the management of the provincial budget for all cancer systemic therapies. The BCOD contains detailed demographic, pathologic, staging, treatment, and outcome data for women diagnosed with breast cancer referred to the BCCA since January 1, 1989. Information on the date and site of first local, regional, or distant relapse is collected prospectively. Date and cause of death is collected from the provincial death registry. The province of British Columbia has a population of approximately 4 million, with close to 2,600 new cases of breast cancer diagnosed annually. Approximately 75% of all cases of breast cancer in the province are referred to a BCCA center.
The following criteria were used to select the cohorts for this study: unilateral invasive breast carcinoma The outcomes of interest were relapse free survival (RFS), breast cancer–specific survival (BCSS), and overall survival (OS). RFS was defined as the time from date of diagnosis to either the first local (breast or chest wall), regional (ipsilateral axillary, infraclavicular, internal mammary or supraclavicular), distant recurrence or death from breast cancer before a recorded relapse. New contralateral breast cancers were not included as an event in RFS. BCSS was defined as the time from date of diagnosis to death where breast cancer was the primary or underlying cause of death. OS was calculated from the time of diagnosis to death from any cause. Kaplan-Meier curves within each cohort were calculated and compared with log-rank tests.
A total of 1,187 cases fulfilling the study criteria were identified from the BCOD. Four hundred thirty cases were identified for cohort 1 (tumor size 0.1–1.0 cm), 507 cases for cohort 2 (1.1 to 2.0 cm) and 250 cases for cohort 3 (2.1–5.0 cm). The median tumor size within each cohort was 0.8 cm (cohort 1), 1.5 cm (cohort 2) and 2.7 cm (cohort 3) respectively. The median follow-up of the entire series was 10.4 years. The median age of this series was 62 years, with a range of 19 to 89 years. Overall, a median of 10 lymph nodes (range, 1 to 60) were retrieved at axillary dissection and was not significantly different between cohorts. 90% of the tumors were infiltrating ductal, 8% infiltrating lobular, and 2% other histologic subtypes. Fifty-two percent of the tumors were estrogen receptor (ER) positive, 21% were ER negative, and 27% were hormone receptor status unknown. Overall, 42% patients underwent a mastectomy, 54% had breast-conserving surgery followed by breast irradiation and 4% had breast-conserving surgery alone. No patient in this series had received adjuvant systemic therapy. Overall at last follow-up 284 subjects (24%) had relapsed, 144 (12%) had died from breast cancer, and 312 (26%) had died from any cause (including breast cancer).
RFS
It is noteworthy that in cohort 2 (1.1–2.0 cm) grade 2 tumors (n = 284) the 5-year relapse rate was 13%, which increased to 26% at 10 years of follow-up. Likewise, in cohort 1 (0.1 to 1.0 cm) grade 3 tumors (n = 115) the 5-year relapse rate was 14%, and increased to 26% at 10 years. There was a general continuing rate of breast cancer relapse between 5 and 10 years, except in grade 1 T1 tumors. Thus grade confers important prognostic information in the natural history of risk of recurrence of breast cancer not treated with adjuvant systemic therapy. RFS based on hormone receptor status (ER positive, ER unknown, and ER negative) is illustrated in Figure 1B. Though the 5-year RFS trended to be better in the ER positive and unknown cohorts versus the ER negative cohort (84%, 88% versus 80% respectively), at 10 years there was no difference in RFS between the cohorts (76%, 77% and 76% respectively; P = .74). This time dependence phenomenon of the prognostic significance of the estrogen receptor, where the initial improved prognosis appears not to be sustained with longer follow-up, has been recognized by others assessing the long-term prognostic significance of the estrogen receptor in breast cancer.12–14 The sites of first recurrence also provide an interesting insight into the natural history of recurrence among competing prognostic factors. Cohort 3 (2.1–5.0 cm) had a statistically higher regional (P = .003 and P = .02) and distant relapse rate (P < .001 and P = .008) than cohorts 1 and 2 respectively. In cohorts 2 and 3, the number of distant relapses outnumbered local and/or regional recurrences (53% and 59% experienced distant relapse first in cohorts 2 and 3, respectively, v 43% in cohort 1; P = .003 and P < .001), whereas in cohort 1, the percentage of first local events (51%) was greater than the number of first distant events. Focusing specifically on cohort 1 (n = 430), 87% of all events occurred in tumors 0.6 to 1.0 cm and 84% of all events occurred in tumors grade 2 or 3. The distribution of first relapses based on the three cohorts is illustrated in Table 2.
BCSS The Kaplan-Meier curves for BCSS for the three cohorts, further categorized by tumor grade, are shown in Figure 3. Overall the 10-year BCSS for cohort 1 was 92%, for cohort 2 was 90%, and for cohort 3 was 77%. These results parallel that seen with the RFS rates above in that a continuation of breast cancer deaths occurs from year 5 to year 10. Of particular note are the subjects within cohort 1 with a grade 3 tumor, the risk of breast cancer death was only 3% at year 5, but increased to 12% at year 10. Thus it also appears grade is an important predictor of risk of breast cancer death within the first 10 years of diagnosis, for all three cohorts with high grade tumors had a disease-specific death rate of 12% or greater. Only low-grade tumors in cohort 1 and 2 and intermediate-grade tumors in cohort 1 had relatively low 10-year breast cancer death rates (3% to 7%).
OS 10-year OS rates were 79%, 78% and 66% for cohorts 1, 2 and 3 respectively. The Kaplan-Meier curves for all 3 cohorts, categorized by grade, are shown in Figure 4. As illustrated, the 10-year death rates, from any cause, are significantly higher than at 5 years. By comparing the breast cancer death rates to the overall death rates, it reveals that patients with relatively low risk disease (grade 1, T size  2 cm; grade 2, T size 1.0 cm) have a greater probability (2:1 ratio or greater) of dying from another cause than dying from their breast cancer. In contrast the highest risk cohorts (grade 3, T size > 1.0 cm; grades 2 T size > 2 cm) had a greater probability (2:1 ratio or greater) of dying as a result of breast cancer than of another cause.
The data from this large series of stage I and II axillary lymph node-negative breast cancer patients not receiving adjuvant systemic therapy with at least 10 years of follow-up provides insight into the natural history of early breast cancer. This study demonstrates the importance of factors such as tumor size, grade, and duration of follow-up in describing frequency and sites of breast cancer events in this cohort of patients. There have been several other large series of breast cancer outcomes with long-term follow-up in the literature, with varying 5- to 10-year outcomes.15–19 An often-quoted study gives the breast cancer survival rates of 24,740 breast cancer cases from the Surveillance, Epidemiology and End-Results (SEER) database.15 The study, however, only reported 5-year outcomes, was a heterogeneous population of patients treated and untreated with adjuvant systemic therapy, and reported BCSS and OS but not RFS rates. The reported 5-year BCSS in a node-negative cohort with a tumor size less than 2 cm was 96.3%. The 5 year BCSS for a similar cohort in our series (cohorts 1 and 2) was 96.5%, but at 10-year the BCSS was 89.6%. Thus this study illustrates the continued event rate beyond 5 years and the importance of long-term outcome evaluation in breast cancer. Size is an important prognostic factor in the absence of axillary lymph node involvement, as illustrated by others.15–17 All tumors in our series over 1 cm, except grade 1 tumors from 1.1 to 2 cm, had a 10-year relapse rate over 25%. This parallels the results from a series of 767 women with T1N0M0/T2N0M0 breast cancer from Memorial Sloan Kettering (MSK) with long-term follow-up (median, 18 years) also not treated with systemic adjuvant therapy.17 In that series tumors greater than 1 cm had a 10-year relapse rate of 27%. However our series also demonstrates the importance of the interaction of grade within defined size cohorts. Grade 3 tumors from 0.1–1.0 cm had a 10-year RFS rate of 74%. This was statistically different from the grade 1 and 2 tumors within the same size cohort (P = .007). Our results differ than the MSK series, which reported a favorable outcome in all tumors less than 1 cm (10-year RFS 91%). Thus the addition of grade to size adds an important further refinement in risk stratification, particularly in small tumors. There have been two other published series of long-term breast cancer outcomes, both within breast cancer screening studies.18–19 Though both studies have long-term follow-up (12–14 years), the only reported breast cancer outcome was cumulative survival. The Swedish two-county study demonstrated relatively favorable outcomes, with node-negative tumors less than 1.5 cm having 12-year OS rates of greater than 90%, regardless of grade. Likewise, the 14-year adjusted survival rates reported from the Breast Cancer Detection and Demonstration Project (BCDDP) of node-negative tumors less than 1.0 cm and 1.0 to 1.9 cm were 92.7% and 91.3%, respectively. In our series the 10-year OS rates for cohorts of the same size ranged from 75% to 83%. As both were screening studies, the upper age limit was 69 to 74 years, this was a younger patient population than in our study. Likewise, due to the volunteer nature of the subjects in both series' the outcomes may not be comparable to that of a general population of breast cancers. The results of this study should aid patients and physicians in the decision-making regarding the relative benefits and risks of adjuvant systemic therapy for early breast cancer. To first understand the potential benefits of adjuvant systemic therapy, the natural history of the disease untreated must be known. In a survey sent to 562 breast cancer survivors in the United States, of which 318 received adjuvant chemotherapy, only 39% of women recalled receiving quantitative estimates of their prognosis and only 31% of women recalled receiving a quantitative estimate both with and without adjuvant therapy.20 In the patients who responded to the survey with stage I breast cancer, their estimates of recurrence if they had not received adjuvant systemic therapy ranged from 7.5% to 100%. There is even significant variation in oncologists' perception of long-term outcomes in an untreated population. In a questionnaire sent to 11 breast cancer medical oncologists in the United States, the 10-year disease free survival based on various prognostic scenarios was asked.21 In the scenario of a node-negative tumor less than 1 cm, the estimated 10-year disease free survival without adjuvant systemic therapy ranged from 80% to 98% (mean 90%). Thus there is significant variability in perceived long-term outcomes by both patients and physicians. The results of this study can be used to facilitate a better understanding of outcomes with and without adjuvant systemic therapy in an individual woman with early breast cancer based on current standard pathologic primary tumor characteristics. The results of this study can also be used to validate currently available tools used as aids in decision making regarding the benefits of adjuvant therapy. Adjuvant! is one such program.22 The program projects outcomes with and without adjuvant therapy based on estimates of prognosis derived from the SEER data registry measured at 5 years and estimates of the efficacy of adjuvant therapy based on the 1998 EBCTCG overviews. The SEER registry–derived data has certain limitations, including the lack of information on relapse status and breast cancer specific mortality. The program Adjuvant! estimates the breast cancer related mortality indirectly from total survival after adjustment for expected age-adjusted natural mortality. Thus the actual relapse rate, sites of first relapse and breast cancer specific survivals from our study can help validate and refine these tools, which can be very useful for both clinicians and patients. Such a validation study using Adjuvant! is currently underway. A limitation of this study is the inability to report on the detailed pathology, staging and outcome for women not referred to a BCCA center. Though the majority of patients in the province of British Columbia are referred to a regional cancer center, approximately 25% are not.23 Prior studies on node-negative breast cancer in British Columbia have shown that patients with worse prognostic features, thus an indication for adjuvant systemic therapy, are more likely to be referred to the BCCA.24–25 In 1991, which is within the time frame of our current study cohort, 26% of all incident cases of node-negative breast cancer in British Columbia received some form of adjuvant systemic therapy.24 Factors associated with the use of adjuvant chemotherapy were younger age, larger tumor size, poor tumor grade, and negative ER status while factors associated with the use of adjuvant tamoxifen in the post menopausal population were larger tumor size, LV involvement and poor tumor grade. Thus it is possible that a greater proportion of patients with node-negative breast cancer with low risk features treated with mastectomy were not referred to the BCCA. Regardless, the cohort of this current study is still one of the largest published to date with long-term follow-up and detailed breast cancer outcomes. In conclusion, results of this study demonstrate the continued relapse rate of low risk, node-negative breast cancer over a 10-year period in a cohort of 1,187 cases not treated with adjuvant systemic therapy. The outcomes categorized by size and grade should be useful to physicians and patients for individualized decision-making regarding the absolute benefits of adjuvant chemotherapy and/or hormonal therapy. Although the majority of patients with node-negative, lymphatic and vascular invasion–negative breast cancer will not relapse, even without adjuvant systemic therapies, both size and grade are important prognostic factors. These results do support the St Gallen's guidelines of adjuvant treatment of early breast cancer.3 The hope is that future factors or classifications, such as gene expression profiling,26 may refine and be more accurate at predicting clinical outcome such that more women with breast cancer and good outcomes can be spared the unnecessary toxicity of adjuvant treatment.
The following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Received more than $2,000 a year from a company for either of the last 2 years: Stephen K. Chia, Schering Canada, Roche, Aventis, Amgen.
Presented in part at the 39th American Society of Clinical Oncology Annual Meeting, May 18–21, 2002, Orlando, FL. Authors' disclosures of potential conflicts of interest are found at the end of this article.
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17. Rosen PP, Groshen S, Kinne DW, et al: Factors influencing prognosis in node negative breast carcinoma: Analysis of 767 T1N0M0/T2N0M0 patients with long term follow-up. J Clin Oncol 11:2090–2100, 1993 18. Tabar L, Fagerberg G, Day NE, et al: Breast cancer treatment and natural history: New insights from results of screening. Lancet 339:412–414, 1992[CrossRef][Medline] 19. Smart CR, Hartmann WH, Beahrs OH, et al: Insights into breast cancer screening of younger women. Cancer 72:1449–1456, 1993[CrossRef][Medline] 20. Ravdin PM, Siminoff LA, Harvey JA: Survey of breast cancer patients concerning their knowledge and expectations of adjuvant therapy. J Clin Oncol 16:515–521, 1998[Abstract]
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22. Ravdin PM, Siminoff LA, Davis GJ, et al: Computer program to assist in making decisions about adjuvant therapy for women with early breast cancer. J Clin Oncol 19:980–991, 2001 23. Olivotto IA, Mates D, Kan L, et al: Prognosis, treatment and recurrence of breast cancer for women attending or not attending the Screening Mammography Program of British Columbia. Breast Cancer Res Treat 54:73–81, 1999[CrossRef][Medline]
24. Olivotto IA, Coldman AJ, Hislop TG, et al: Compliance with practice guidelines for node-negative breast cancer. J Clin Oncol 15:216–222, 1997 25. Sawka C, Olivotto IA, Coldman A, et al: The association between population-based treatment guidelines and adjuvant therapy for node-negative breast cancer. Br J Cancer 75:1534–1542, 1997[Medline] 26. van't Veer LJ, Dal H, and van de Vijver MJ, et al: Gene expression profiling predicts clinical outcome of breast cancer. Nature 415:530–536, 2002[CrossRef][Medline] Submitted September 12, 2003; accepted February 11, 2004.
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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
25% 10-year risk of relapse and a corresponding 10-year breast cancer death rate of 
